Title: Targeting Muller Cells to Treat Optic Nerve Injury Principal Investigator: Sherry L. Ball, PhD Objectives: A substantial proportion of returning veterans diagnosed with traumatic brain injuries (TBI) also exhibit visual deficits. The VA Polytrauma Rehabilitation Center in Palo Alto, CA, has reported that approximately 70% of their traumatic brain injury patients experience visual deficits. Given the large proportion of returning soldiers from Operation Enduring Freedom and Operation Iraqi Freedom with traumatic brain injury it is clear that studies investigating how ocular trauma affect retinal and visual function are urgently needed. Our goal is to identify the underlying signals triggering degenerative processes in the retina. It is well established that both glial and neuronal cells in the retina respond to ocular trauma. Recent studies suggest that neuronal degeneration is exacerbated by glial cell reactivity. We hypothesize that alterations in glial cell function contribute to vision losses and that the modulation of glial cell reactivity will minimize retinal degeneration and thus vision loss. Research Plan: We will test the hypothesis that a) loss of vision following TBI involves reactive events triggered by retinal Muller cells and b) that retinal degeneration and vision loss can be prevented or slowed by treatment with anti-inflammatory agents which target Muller cells. Methodology: Electroretinography (ERG) will be used to noninvasively follow retinal function and injury responses in the retina using no b-wave (nob) and wild type (WT) mice following optic nerve crush. The nob mouse is a naturally occurring mutant mouse in which M|ller cell function as represented in the ERG is unmasked due to the loss of the bipolar cell response while photoreceptor function is maintained. This means that both photoreceptor function and Muller cell function can be followed by ERG in nob mice following experimentally induced optic nerve injury. We will track retinal Muller cell and photoreceptor function using ERG and a behavioral test to measure visual acuity in mice treated with minocycline before and after experimentally induced optic nerve injury. Visual performance in an optokinetic reflex test will be used to measure visual acuity. Tissue will be collected at the end of the study to identify signaling mechanisms involved in reactive gliosis and subsequent cellular events. Clinical Significance: TBI is an increasingly significant issue facing Operation Enduring Freedom and Operation Iraqi Freedom veterans. This proposal will test a treatment strategy to preserve or restore visual function to individuals with ocular injuries. In addition, we will more clearly define the role of glial cells in neural degeneration following trauma. PUBLIC HEALTH RELEVANCE Significance of Research: Patients with TBI resulting from blast injury display an array of visual deficits collectively referred to as Post Trauma Vision Syndrome (Padula et al., 1988;Jackowski et al, 1996;Goodrich et al., 2007). Some portion of this visual syndrome is believed to be due to concussive forces to the head which transmit a shock wave to the optic canal, damaging the optic nerve. In fact, the prevalence of optic nerve damage is thought to be so great that ultrasonography of the optic nerve has recently been suggested as a diagnostic measure for TBI (Geeraerts et al., 2007;Kimberly et al. 2008, Soldatos et al., 2008;Tayal et al., 2007 ). The primary glial cell type in the retina, M|ller cell, is known to undergo reactive changes in response to optic nerve injury. Because M|ller cells are fundamental to the maintenance of retinal cell function, reactive events following optic nerve injury can result in loss of retinal and visual function. We propose to test the ability of pharmacological agents, beginning with minocycline, which target retinal M|ller cells to prevent or slow injury responses. Reactive gliosis triggers events resulting in the release of pro-inflammatory agents by M|ller cells that promote secondary damage in nearby neurons as well as the release of neurotrophic factors to support cell survival. Therefore, understanding how to modulate the activity of retinal M|ller cells is most likely elemental to the development of therapeutic strategies for all forms of injury induced retinal degeneration. Relevance of the Proposed Work to the VA Patient Care Mission Research related to blast exposure is currently of high priority to the VA as many returning soldiers from Operation Iraqi Freedom and Operation Enduring Freedom suffer from these types of injuries. This proposal will develop better diagnostic protocols for visual function in TBI patients and will test a treatment strategy to preserve or restore visual function to individuals with blast associated optic nerve injuries. Positive results will be further explored to develop optimal treatment strategies.